Piperdine compounds and their preparation and use

ABSTRACT

The present invention relates to therapeutically active piperidine compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer&#39;s disease, severe painful conditions and glaucoma.

CROSS-REFERENCE TO RELATED U.S. APPLICATION

This application is a divisional of Ser. No. 08/472,356, filed Jun. 7,1995, which is a continuation of Ser. No. 08/144,951, filed Oct. 29,1993, now abandoned which is a divisional of Ser. No. 07/745,568, filedAug. 15, 1991 now U.S. Pat. No. 5,284,859, which is a continuation ofSer. No. 07/482,272, filed Feb. 20, 1990, now U.S. Pat. No. 5,041.455,which is a Continuation-in-Part of U.S. patent application Ser. No.07/401,370 filed on 31 Aug. 1989, now U.S. Pat. No. 5,043,345.

Due to the in general improved health situation in the western world,elderly-related diseases are much more common now than in the past andare likely to be even more common in the future.

One of the elderly-related symptoms is a reduction of the cognitivefunctions. This symptom is especially pronounced in thepathophysiological disease known as Alzheimer's disease. This disease iscombined with, and also most likely caused by, a up to 90% degenerationof the muscarinic cholinergic neurons in nucleus basalis, which is partof substantia innominata. These neurons project to the prefrontal cortexand hippocampus and have a general stimulatory effect on the cognitivefunctions of the forebrain as well as of hippocampus, namely learning,association, consolidation, and recognition.

It is a characteristic of Alzheimer's disease that although thecholinergic neurons degenerate, the postsynaptic muscarinic receptors inthe forebrain and hippocampus still exist. Therefore, muscariniccholinergic agonists are useful in the treatment of Alzheimer's diseaseand in improving the cognitive functions of elderly people.

It is well known that arecoline (methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergicagonist (See Formula A) ##STR1##

Arecoline, however, has a very short biological half life and a smallseparation between central and peripheral muscarinic effects.Furthermore, arecoline is a rather toxic compound. It is also known that3-acetoxy-quinuclidine is a muscarinic agonist (See Formula B) ##STR2##However, the disadvantages of this compound are the same as indicatedfor arecoline.

It is, therefore, an object of the present invention to provide newmuscarinic cholinergic compounds having different structures anddifferent levels of activity.

The novel compounds of the invention are of formula I: ##STR3## whereinZ is oxygen or sulphur, R is H, C₁₋₃ -alkyl, C₃₋₄ -cycloalkyl, C₂₋₄-alkenyl or C₂₋₄ -alkynyl and R¹ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅-alkynyl, C₃₋₇ -cycloalkyl, C₄₋₈ -cycloalkylalkyl, phenoxy, benzyloxy,morpholino, C₁₋₆ -alkyl substituted piperidino, halogen, amino, C₁₋₆-acylamino, C₁₋₁₅ -alkylamino, C₁₋₁₅ -dialkylamino, C₁₋₁₅ -alkoxyamino,alkoxyamino, S--R² or O--R² wherein R² is straight or branched C₁₋₁₅-alkyl, straight or branched C₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅-alkynyl R³ --O--R⁴, R³ --NH--R⁴, R³ --S--R⁴, R³ --O--R⁴ --O--R⁵ whereinR³, R⁴ and R⁵ independently are C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅-alkynyl or a salt thereof with a pharmaceutically-acceptable acid.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate, or similarpharmaceutically-acceptable and organic acid addition salts.

This invention also includes a method for producing compounds of formulaI with alkylation and reduction reactions of the appropriate pyridinecompounds. In addition, the invention herein further comprisespharmaceutically compositions incorporating the compounds of formula Ialong with methods for treating Alzheimer's disease with thesecompounds.

The compounds of this invention are also useful analgesic agents andtherefore useful in the treatment of severe painful conditions.

Furthermore, the compounds of this invention are useful in the treatmentof glaucoma.

The invention comprises a method of preparing 3-(1,2,5-oxadiazol-3-yl)or 3-(1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridine compounds havingthe general formula I: ##STR4## by alkylating a compound having theformula II ##STR5## with an alkyl halide and reducing the compound thusformed with hydride ions to form a compound having the formula I##STR6## wherein Z is oxygen or sulphur, R is H, C₁₋₃ -alkyl, C₃₋₄-cycloalkyl, C₂₋₄ -alkenyl or C₂₋₄ -alkynyl and R¹ is C₁₋₁₅ -alkyl,C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, C₃₋₇ -cycloalkyl, C₄₋₈ -cycloalkylalkyl,phenoxy, benzyloxy, morpholino, C₁₋₆ -alkyl substituted piperidino,halogen, amino, C₁₋₆ -acylamino, C₁₋₁₅ -alkylamino, C₁₋₁₅ -dialkylamino,C₁₋₁₅ -alkoxyamino, S--R² or O--R² wherein R² is straight or branchedC₁₋₅ -alkyl, straight or branched C₂₋₁₅ -alkenyl, straight or branchedC₂₋₁₅ -alkynyl R³ --O--R⁴, R³ --NH--R⁴, R³ --S--R⁴, R³ --O--R⁴ --O--R⁵wherein R³, R⁴ and R⁵ independently are C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl,C₂₋₁₅ -alkynyl or a salt thereof with a pharmaceutically-acceptableacid.

All of the below shown structures are known to have affinity for themuscarinic receptors, but only the 3-alkyl-1,2,4-oxadiazol-5-yls (Illand VII) and the 3-alkyl-1,2,4-thiadiazol-5-yls (IV and VIII) areagonists. The 5-alkyl-1,2,4-oxadiazol-3-yls (V and IX) and the5-alkyl-1,2,4-thiadiazol-3-yls (VI and X) are antagonists. ##STR7##(wherein R=C₁₋₂ -alkyl)

A common feature for all of the shown heterocycles with affinity formuscarinic receptors is that the substituent (R) always is in the betaposition relative to the cyclic amine: ##STR8##

The difference between XI and XII is in the electronic distribution inthe heterocycle. In other words, in XI the double bonds are in anotherrelative position to the substituent than in XII.

Without wishing to be bound by any theory or mechanism it is believedthat this is probably why structures with the general structure XI aremuscarinic agonists and structures with the general structure XII aremuscarinic antagonists.

It is therefore very surprising that heterocycles with a substituent inthe alpha position to the cyclic amine as with the active compoundsdisclosed and claimed herein are extremely effective ester isosters.There are no known alpha-substituted heterocycles being ester isosters.

For instance,3-(3-subst.-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridines(XIII) have been found to be very potent muscarinic agonists with abetter M₁ -selectivity than agonists with the substituent in the betaposition. ##STR9##

Furthermore, not all alpha-substituted heterocycles are ester isosters.It is believed that the position of the double bonds relative to thesubstituent (R) is very important. If the electrostatic properties aredifferent from the one indicated in the heterocycle of structure XIII,the muscarinic agonist activity decreases dramatically. Compounds withthe general formula XIV are either antagonists or inactive. ##STR10##

The heterocycles with the general formula XV are, therefore, bothstructurally and biologically different from the general structures XI,XII and XIV. ##STR11##

That the compounds XIII fit the muscarinic receptors better than thestructures III to X is reflected in the fact that the substituent (R) isallowed to be bigger and more lipophilic without losing affinity andagonist activity. In fact, it is the C₄₋₈ -alkoxy that show the best M₁-selectivity.

The pharmacological properties of the compounds of the present invention(Formula I) can be illustrated by determining their capability toinhibit the specific binding of ³ H-Oxotremorine-M (³ H-Oxo).

³ H-Oxo labels muscarinic receptors in the CNS (with a preference foragonist domaines of the receptors). Three different sites are labelledby 3H-Oxo. These sites have affinity of 1.0, 20 and 3000 nM,respectively. Using the present experimental conditions only the highand medium affinity sites are determined. The inhibitory effects ofcompounds on ³ H-Oxo binding reflects the affinity for muscarinicacetylcholine receptors.

All preparations are performed at 0°-4° C. unless otherwise indicated.Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenizedfor 5-10 s in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turraxhomogenizer. The homogenizer is rinsed with 10 ml of buffer and thecombined suspension centrifuged for 15 min at 40,000×g. The pellet iswashed three times with buffer. In each step the pellet is homogenizedas before in 2×10 ml of buffer and centrifuged for 10 min at 40,000×g.The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 ml is added25 μl of test solution and 25 μl of ³ H-Oxotremorine (1.0 nM, finalconcentration) mixed and incubated for 30 min at 25° C. Non-specificbinding is determined in triplicate using Arecoline (1 μg/ml, finalconcentration) as the test substance. After incubation samples are added5 ml of ice-cold buffer and poured directly onto Whatman GF/C glassfiber filters under suction and immediately washed 2 times with 5 ml ofice-cold buffer. The amount of radioactivity on the filters aredetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding. Test substances aredissolved in 10 ml water (if necessary heated on a steam-bath for lessthan 5 minutes) at a concentration of 2.2 mg/ml. 25-75% inhibition ofspecific binding must be obtained before calculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration (ng/ml) of thetest substance which inhibits the specific binding of ³ H-Oxo by 50%).##EQU1## where C_(o) is specific binding in control assays and C_(x) isthe specific binding in the test assay. (The calculations assume normalmass-action kinetics).

Test results obtained by testing some compounds of the present inventionwill appear from the following Table 1.

                  TABLE 1                                                         ______________________________________                                                      Inhibition in vitro                                                           OXO BINDING                                                     Compound No.  (ng/ml)                                                         ______________________________________                                         1            1.5                                                              2            0.4                                                              3            0.2                                                              4            0.5                                                              5            3.5                                                              6            1.9                                                              7            1.7                                                              8            1.9                                                              9            3.6                                                             10            2.3                                                             11            0.9                                                             12            0.3                                                             13            0.3                                                             14            0.4                                                             15            0.6                                                             16            3.3                                                             17            19.0                                                            18            3.6                                                             19            92                                                              20            5.9                                                             21            2.4                                                             22            0.4                                                             23            0.3                                                             24            0.4                                                             25            12                                                              26            0.4                                                             27            0.8                                                             28            1.3                                                             29            0.6                                                             30            0.4                                                             31            0.7                                                             32            1.4                                                             33            1.0                                                             34            1.0                                                             35            0.6                                                             36            0.3                                                             37            6.3                                                             38            7.4                                                             40            3.7                                                             41            1.3                                                             42            7.0                                                             43            4.0                                                             44            14                                                              45            115                                                             46            18                                                              47            0.3                                                             48            0.6                                                             49            0.7                                                             50            300                                                             51            300                                                             52            65                                                              53            1.2                                                             54            20                                                              55             8                                                              56            2.1                                                             57            --                                                              58            50                                                              59            --                                                              60            164                                                             61            50                                                              62            32                                                              63            25                                                              64            58                                                              65            0.6                                                             66            1.8                                                             67            1.6                                                             ______________________________________                                    

The compounds of the present invention, together with a conventionaladjuvant, carrier, or diluent, and if desired in the form of apharmaceutically-acceptable acid addition salt thereof, may be placed inthe form of pharmaceutical compositions and unit dosages thereof, and insuch form may be employed as solids, such as tablets or filled capsules,or liquids, such as solutions, suspensions, emulsions, elixirs, orcapsules filled with the same, all for oral use, in the form ofsuppositories for rectal administration; or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective muscarinic cholinergic agonisticamount of the active ingredient commensurate with the intended dailydosage range to be employed. Tablets containing ten (10) milligrams ofthe active ingredient or, more broadly, one (1) to hundred (100)milligrams, per tablet, are accordingly suitable representative unitdosage forms.

The compounds of this invention can thus be used for the formulation ofpharmaceutical preparations, e.g. for oral and parenteral administrationto mammals including humans, in accordance with conventional methods ofgalenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylase, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch, are particularly suitable for oralapplication. A syrup, elixir or the like can, be used in cases where asweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit formcomprising 1-100 mg in a pharmaceutically acceptable carrier per unitdosage.

The dosage of the compounds according to this invention is 1-100 mg/day,preferably 10-70 mg/day, when administered to patients, e.g. humans, asa drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Active compound    5.0    mg                                                  Lactosum           67.8   mg Ph. Eur.                                         Avicel ®       31.5   mg                                                  Amberlite ®    1.0                                                        Magnesii stearas   0.25   mg Ph. Eur.                                         ______________________________________                                    

Due to the high muscarinic cholinergic receptor agonistic activity, thecompounds of the invention are extremely useful in the treatment ofsymptoms related to a reduction of the cognitive functions of the brainof mammals, when administered in an amount effective for stimulating thecognitive functions of the forebrain and hippocampus. The importantstimulating activity of the compounds of the invention includes bothactivity against the pathophysiological disease, Alzheimer's disease, aswell as against normal degeneration of brain function.

The compounds of the invention may accordingly be administered to asubject, e.g., a living animal body, including a human, in need ofstimulation of the cognitive functions of the forebrain and hippocampus,and if desired in the form of a pharmaceutically-acceptable acidaddition salt thereof (such as hydrobromide, hydrochloride, or sulfate,in any event prepared in the usual or conventional manner, e.g.evaporation to dryness of the free base in solution together with theacid), ordinarily concurrently, simultaneously, or together with apharmaceutically-acceptable carrier or diluent, especially andpreferably in the form of a pharmaceutical composition thereof, whereofby oral, rectal, or parenteral (including subcutaneous) route, in aneffective forebrain and hippocampus stimulating amount, and in any eventan amount which is effective for improving the cognitive function ofmammals due to their muscarinic cholinergic receptor agonistic activity.

The compounds of this invention are also useful analgesic agents andtherefore useful in the treatment of severe painful conditions.

Furthermore, the compounds of this invention are useful in the treatmentof glaucoma.

Suitable dosage ranges are 1-100 milligrams daily, 10-100 milligramsdaily, and especially 30-70 milligrams daily, depending as usual uponthe exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and the preferenceand experience of the physician or veterinarian in charge.

The preferred methods for the preparation of the active compounds ofthis invention are illustrated in the following examples in more detail.

EXAMPLE 1

A. 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sulfurmonochloride (2.4 ml, 30 mmol) inN,N-dimethylformamide (5 ml) was slowly added alpha-amino-alpha(3-pyridyl)acetonitril (Archive der Pharmazie 289 (4) (1956)) (1.70 g,10 mmol). The reaction mixture was stirred at room temperature for 18 h.Water (20 ml) was added and the aqueous phase was extracted with etherand the ether phase discharged. A 50% potassium hydroxide solution wasadded to the aqueous phase to pH>9. The aqueous phase was extractedseveral times with ether and the ether phases were dried and evaporated.The residue was purified by column chromatography (SiO₂, eluent: ethylacetate/methylene chloride (1:1)). The title compound was collected in45% (880 mg) yield. M⁺ : 197.

B. 3-(4-methoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (750 mg, 3.8 mmol). Themixture was stirred at 50° C. for 1 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the title compound,which crystallized with petroleum ether in a 630 mg (86%) yield.

C. 3-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.37 ml, 6 mmol) and3-(4-methoxy-1,2,5-thiadiazol-3-yl)pyridine (500 mg, 2.5 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.Yield: 1.0 g (100%).

D.1,2,5,6-tetrahydro-3-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridineoxalate

Sodium borohydride (460 mg, 12 mmol) was added to a solution of3-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (1.0 g, 3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred atroom temperature for 1 h. After evaporation the residue was dissolved inwater and extracted with methylene chloride. The dried organic phaseswere evaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone. Yield: 390 mg. (M.p. 150°C.; M⁺ : 211; Compound 1).

EXAMPLE 2

A. 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (540 mg, 3.3 mmol). Themixture was stirred at 40° C. for 10 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 520 mg (76%) of thetitle compound.

B. 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(4-ethoxy-1,2,5-thiadiazol-3-yl)pyridine (520 mg, 2.5 mmol) in acetone(10 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.72 g (83%).

C.3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.72 g, 2mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred atroom temperature for 1 h. After evaporation the residue was dissolved inwater and extracted with methylene chloride. The dried organic phaseswere evaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone, and recrystallized frommethanol to yield 190 mg. (M.p. 137° C.; M⁺ : 225; Compound 2).

EXAMPLE 3

A. 3-(4-propoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (650 mg, 3.3 mmol). Themixture was stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 700 m (96%) of thetitle compound.

B. 3-(4-propoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.37 ml, 6 mmol) and3-(4-propoxy-1,2,5-thiadiazol-3-yl)pyridine (700 mg, 3.1 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.98 g (88%).

C.1,2,5,6-tetrahydro-1-methyl-3-(4-propoxy-1,2,5-thiadiazol-3-yl)pyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(4-propoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (980 mg,2.7 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 440 mg. (M.p.148° C.; M⁺ : 239; Compound 3).

EXAMPLE 4

A. 3-(4-butoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (290 mg, 12.5 mmol) in n-butanol (10 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to yield 580 mg (100%) of thetitle compound.

B. 3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol ) and3-(4-butoxy-1,2,5-thiadiazol-3-yl)pyridine (580 mg, 2.5 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.60 g (64%).

C.3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (240 mg, 6.4 mmol) was added to a solution of3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.60 g,1.6 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 280 mg. (M.p.158° C.; M⁺ : 253; Compound 4).

EXAMPLE 5

A. 3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with ethyl acetate. The combinedorganic phases were dried and evaporated to yield 540 mg (98%) of thetitle compound.

B. 3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)pyridine (540 mg, 2.4 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.68 g (77%).

C.1,2,5,6-tetrahydro-3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridineoxalate

Sodium borohydride (280 mg, 7.2 mmol) was added to a solution of3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (650mg, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 280 mg. (M.p.164° C.; M⁺ : 239; Compound 5).

EXAMPLE 6

A. 3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in 1-pentanol (20 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 3 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the wanted compound.

B. 3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.3 ml, 5 mmol) and3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)pyridine (620 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.81 g (84%).

C.1,2,5,6-tetrahydro-1-methyl-3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)pyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.81 g,2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ether. The dried organic phases were evaporated andthe residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone, and recrystallized from methanol to yield 220mg. (M.p. 150° C.; M⁺ : 267; Compound 6).

EXAMPLE 7

A. 3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in isobutanol (10 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 3 h and evaporated. The residue wasdissolved in water and extracted with methylene chloride. The combinedorganic phases were dried and evaporated to give the wanted compound.

B. 3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide

A mixture of methyl iodide (0.6 ml, 10 mmol) and3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)pyridine (588 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.88 g (87%).

C.1,2,5,6-tetrahydro-3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridineoxalate

Sodium borohydride (160 mg, 4.3 mmol) was added to a solution of3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.82 g,2.2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat O° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 400 mg. (M.p.135° C.; M⁺ : 253; Compound 7).

EXAMPLE 8

A. 3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 10 mmol) and3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)pyridine (622 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.78 g (81%).

C.1,2,5,6-tetrahydro-3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (780mg, 2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 350 mg. (M.p.152° C.; M⁺ : 267; Compound 8).

EXAMPLE 9

A. 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) was added3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (658 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.81 g (80%).

C.3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (810 mg,2 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat room temperature for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 350 mg. (M.p.148° C.; M⁺ : 281; Compound 9).

EXAMPLE 10

A. 3-(4-benzyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (490 mg, 2.5 mmol) in benzyl alcohol (15 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). Themixture was stirred at 50° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the wanted compound.

B. 3-(4-benzyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-benzyloxy-1,2,5-thiadiazol-3-yl)pyridine (673 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.75 g (73%).

C.3-(4-benzyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-benzyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (750 mg,1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat 0° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 340 mg. (M.p.149° C.; M⁺ : 287; Compound 10).

EXAMPLE 11

A. 3-(4-(3-butenyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 3-buten-1-ol (540 mg, 7.5 mmol) and sodium hydride (180mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 m, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 650 m of the titlecompound.

B. 3-(4-(3-butenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-(3-butenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (583 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 890 mg (96%).

C.3-(4-(3-butenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.5 mmol) was added to a solution of3-(4-(3-butenyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(1.03 g, 2.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)).

The title compound was crystallized as the oxalate salt from acetone toyield 380 mg. (M.p 141° C.; M⁺ : 251; Compound 11).

EXAMPLE 12

A. 3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodiumhydride (180mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)pyridine (578 mg, 2.5 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.88 g (95%).

C.3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (180 mg, 4.7 mmol) was added to a solution of3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.88 g, 2.35 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone, and recrystallized inmethanol to yield 140 mg. (M.p. 158° C.; M⁺ : 249; Compound 12).

EXAMPLE 13

A. 3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of propargyl alcohol (420 mg, 7.5 mmol) and sodium hydride(180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 530 mg (98%) of the titlecompound.

B. 3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.45 ml, 7.2 mmol) and3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)pyridine (430 mg, 2.4 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.58 g (67%).

1,2,5,6-tetrahydro-1-methyl-3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)pyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.68g, 1.9 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at 0° C. for 1 h. After evaporation the residue was dissolved inwater and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 200 mg. (M.p.155° C.; M⁺ : 235; Compound 13).

EXAMPLE 14

A. 3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride(110 m, 5 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 3 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to yield 400 m (69%) of the titlecompound.

B. 3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-Yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.25 ml, 4 mmol) and3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl)pyridine (400 mg, 1.7mmol) in acetone (5 ml) was stirred at room temperature for 36 h. Thetitle compound precipitated from the solution and was collected byfiltration to yield 0.41 (65%).

C.3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (170 mg, 4.4 mmol) was added to a solution of3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(410 mg, 1.1 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at 0° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 130 mg. (M.p.153° C.; M⁺ : 251; Compound 14).

EXAMPLE 15

A. 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.98 g, 10mmol) and methyl iodide (4.25 g, 30 mmol) in acetone (10 ml) was stirredat room temperature for 16 h. The precipitate was collected byfiltration to yield 3.40 g (100%) of the title compound.

B.3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

To a suspension of sodium borohydride (330 mg, 8.6 mmol) in ethanol (20ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (1.46 g, 4.3 mmol) at 0° C. The reaction mixture was stirred for1 h at 0° C. Water was added and the mixture was extracted with ethylacetate. After drying, the ethyl acetate phase was evaporated and theresidue purified by column chromatography (eluent: ethylacetate:methanol (4:1)). Yield: 880 mg (95%). Crystallization withoxalic acid from acetone gave the title compound. (M.p. 124° C.; M⁺ :215 and 217; Compound 16).

1,2,5,6-tetrahydro-3-(4-methoxyethoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridineoxalate

To a solution of sodium (120 mg, 5 mmol) in 2-methoxyethanol (10 ml) wasadded3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (310 mg, 1 mmol). The mixture was stirred at 50° C. for 18 h andevaporated. The residue was dissolved in water and extracted with ethylacetate. The combined organic phases were dried and evaporated. Thetitle compound was crystallized as the oxalate salt from acetone toyield 270 mg. (M.p. 152.1° C.; M⁺ : 253; Compound 15).

D. 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridinehydrochloride

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(670 mg, 3.1 mmol) in 1,2-dichloroethane (20 ml) was added a solution of1-chloro-methyl-chloroformate (440 mg, 3.1 mmol) in 1,2-dichloroethaneat 0° C. The reaction mixture was heated to 40° C. for 2 h andevaporated. The residue was dissolved in methanol and heated to refluxfor 1 h. After cooling to room temperature the precipitate was collectedby filtration to yield 320 mg (41%). (M.p. 224° C.; M⁺ : 201 and 203;Compound 17).

E. 3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridine oxalate

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (15 ml) wasadded 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridinehydrochloride (240 mg, 1 mmol). The reaction mixture was stirred at 50°C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The ethyl acetate phase was dried andevaporated to give an oil (200 mg). Crystallization as the oxalate saltfrom acetone gave the title compound. Yield: 170 mg (52%). (M.p.173-174° C.; M⁺ : 239; Compound 18).

EXAMPLE 16

A. 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-ethylpyridinium iodide

A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.13 g, 5.7mmol) and ethyl iodide (22.65 g, 17 mmol) in acetone (15 ml) was stirredat 40° C. for 16 h. The precipitate was collected by filtration givingthe title compound. Yield: 510 mg (26%).

B. 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-ethyl-1,2,5,6-tetrahydropyridineoxalate

To a suspension of sodium borohydride (170 mg, 4.5 mmol) in ethanol (10ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-ethylpyridiniumiodide (510 mg, 1.5 mmol) at 0° C. The mixture was stirred for 1 h at 0°C. Water was added and the mixture was extracted with ethyl acetate.After drying, the ethyl acetate phase was evaporated and the residuepurified by column chromatography (eluent: ethyl acetate/methanol(4:1)). Crystallization with oxalic acid from acetone gave the titlecompound to yield 70 (M.p. 143° C.; M⁺ : 229 and 231; Compound 19).

EXAMPLE 17

A. 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-ethylpyridinium iodide

A solution of 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)pyridine (0.90 g, 4.3mmol) and ethyl iodide (2.03 g, 13 mmol) in acetone (4 ml) was stirredat 40° C. for 16 h. The precipitate was collected by filtration givingthe title compound to yield 1.34 g (86%).

B. 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-ethyl-1,2,5,6-tetrahydropyridineoxalate

To a suspension of sodium borohydride (410 mg, 10.8 mmol) in ethanol (10ml) was added 3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-ethylpyridiniumiodide (1.32 g, 3.6 mmol) at 0° C. The mixture was stirred for 1 h at 0°C. Water was added and the mixture was extracted with ethyl acetate.After drying, the ethyl acetate phase was evaporated and the residuepurified by column chromatography (eluent: ethyl acetate/methanol(4:1)). Crystallization with oxalic acid from acetone gave a yield of0.49 g of the title compound. (M.p. 120°-122° C.; M⁺ : 239; Compound20).

EXAMPLE 18

3-(4-heptyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

To a solution of sodium (120 mg, 5 mmol) in 1-heptanol (10 ml) was added3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (310 mg,1 mmol). The reaction mixture was stirred at 50° C. for18 h. After evaporation the residue was dissolved in water and extractedwith ethyl acetate. The ethyl acetate phase was dried and evaporated togive an oil. Crystallization as the oxalate salt from acetone gave thetitle compound. Yield: 270 mg (70%). (M.p. 152° C.; M⁺ : 295; Compound21).

EXAMPLE 19

A. 3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.6 ml, 9 mmol) and3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(10 ml) was stirred at room temperature for 18 h.

The title compound precipitated from the solution and was collected byfiltration to yield 0.68 g (59%).

C.3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.68 g, 1.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 240 mg. (M.p.166°-167° C.; M⁺ : 263; Compound 22).

EXAMPLE 20

A. 3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride(260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (2.5 mmol) inacetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.67 g (69%).

C.3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.67 g, 1.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 150 m. (M.p.141°-142° C.; M⁺ : 265; Compound 23).

EXAMPLE 21

A. 3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310m, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.4 ml, 6 mmol) and3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to give0.96 g (88%).

C.3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.5 mmol) was added to a solution of3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.96 g, 2.6 mmol) in ethanol (99.9%, 25 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 270 mg. (M.p.136°-137° C.; M⁺ : 237; Compound 24).

EXAMPLE 22

A. 3-(4-octyloxy-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (350 g, 15 mmol) in 1-octanol (10 ml) was added3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol). The mixturewas stirred at 50° C. for 1 h and evaporated. The residue was dissolvedin water and extracted with methylene chloride. The combined organicphases were dried and evaporated to give the title compound.

B. 3-(4-octyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-octyloxy-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (5 ml)was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.81 g (62%).

C.3-(4-octyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (210 mg, 5.6 mmol) was added to a solution of3-(4-octyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (0.81 g,1.87 mmol) in ethanol (99.9%, 10 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 330 mg. (M.p.144°-145° C.; M⁺ : 309; Compound 25).

EXAMPLE 23

A. 3-(4-(3-hexynyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 3-hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(3-hexynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-(3-hexynyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.85 g (71%).

C. 3-(4-(3-hexynyloxy) -1,2, 5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(4-(3-hexynyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.85 g, 2.1 mmol) in ethanol (99.9%, 10 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 350 mg. (M.p.174°-175° C.; M⁺ : 277; Compound 26).

EXAMPLE 24

A. 3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of 3-methyl-2-buten-1-ol (780 mg, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 0.3 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B.3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (3 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.92 g (79%).

C.3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (220 mg, 6 mmol) was added to a solution of3-(4-(3-methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (0.92 g, 2.3 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 380mg. (M.p. 150°-151° C.; M⁺ : 265; Compound 27).

EXAMPLE 25

A. 3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 3-buten-2-ol (650 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 18 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (3 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.73 g (65%).

C.3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.73 g, 1.9 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 270 mg. (M.p.134°-135° C.; M⁺ : 251; Compound 28).

EXAMPLE 26

A. 3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 4-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.54 g (45%).

C.3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.54 g, 1.3 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 190 mg. (M.p.151°-152° C.; M⁺ : 279; Compound 29)

EXAMPLE 27

A. trans-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. trans-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) and trans-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (5 ml)was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.90 g (75%).

C.trans-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution oftrans-3-(4-(3-hexenyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (0.90 g, 2.2 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 420mg. (M.p. 163°-164° C.; M⁺ : 279; Compound 30).

EXAMPLE 28

A. cis-3-(4-(2-pentenyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of cis-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(4-(2-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (1 ml, 15 mmol) andcis-3-(4-(2-pentenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.53 g (46%).

C.cis-3-(4-(2-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution ofcis-3-(4-(2-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (0.53 g, 1.3 mmol) in ethanol (99.9%, 15 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 210mg. (M.p. 143°-144° C.; M⁺ : 265; Compound 31).

EXAMPLE 29

A. cis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

5 A mixture of methyl iodide (0.5 ml, 7.5 mmol) andcis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (4 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.

C.cis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution ofcis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.6 g, 1 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 150 mg. (M.p.122°-123° C.; M+: 279; Compound 32).

EXAMPLE 30

A. 3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) and3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield0.75 g (62%).

C.3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-(5-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.75 g, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 250 mg. (M.p.137°-138° C.; M⁺ : 279; Compound 33).

EXAMPLE 31

A. cis-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of cis-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. cis-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0,5 ml, 7.5 mmol) andcis-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.9 g (46%).

C.cis-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution ofcis-3-(4-(3-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(0.90 g, 2.2 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 0.5 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 300 mg. (M.p.149°-150° C.; M⁺ : 279; Compound 34).

EXAMPLE 32

A. trans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. trans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 7.5 mmol) andtrans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 1.09 g (90%).

C.trans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 4 mmol) was added to a solution oftrans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (1.09 g, 2.7 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 0.5 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 400mg. (M.p. 130°-131° C.; M⁺ : 279; Compound 35).

EXAMPLE 33

A. 3-(1,2,5-thiadiazol-3-yl)pyridine

To a solution of 1-butanethiol (2.7 g, 30 mmol) and sodium hydride (1.2g, 30 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.2 g, 6 mmol) in drytetrahydrofuran. The reaction mixture was stirred at -10° for 0.5 h.Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methylene chloride (1:1)) togive the title compound.

B. 3-(1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(1,2,5-thiadiazol-3-yl)pyridine (6 mmol) in acetone (5 ml) was stirredat room temperature for 18 h. The title compound precipitated from thesolution and was collected by filtration to yield 1.2 g (74%).

C. 3-(1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (380 m, 10 mmol) was added to a solution of3-(1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (1.2 g 4.4 mmol) inethanol (99.9%, 20 ml) and the reaction mixture was stirred at -10° C.for 0.5 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 430 mg (M.p 189°-190° C.; M⁺ : 181;Compound 36).

EXAMPLE 34

1,2, 5,6-tetrahydro-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl) pyridineoxalate

To a solution of3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(0.70 g, 2.4 mmol) in 1,2-dichloroethane (20 ml) was added a solution of1-chloromethyl-chloroformate (0.35 g, 2.4 mmol) in 1,2-dichloroethane at0° C. The reaction mixture was treated to 40° C. for 2 h and evaporated.The residue was dissolved in methanol and heated to reflux for 1 h andevaporated. The residue was dissolved in diluted sodium hydroxide andextracted with ether. The combined ether phases were dried andevaporated. Crystallization as the oxalate salt from acetone gave thetitle compound in 72% (620 mg) yield. (M.p. 157°-159° C.; M⁺ : 267;Compound 37).

EXAMPLE 35

A. 3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of sodium (210 mg, 9 mmol) in 2-(2-methoxy-ethoxy)ethanol(10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3mmol). The mixture was stirred at 50° C. for 4 h and evaporated. Theresidue was dissolved in water and extracted with ether. The combinedorganic phases were dried and evaporated to give the title compound.

B.3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol)in acetone (10 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 0.76 g (60%).

C.3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (150 mg, 4 mmol) was added to a solution of3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (0.76 g, 1.8 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 1 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 70mg. (M.p. 142°-143° C.; M⁺ : 299; Compound 38).

EXAMPLE 36

3-(4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-3-yl) pyridine

To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-ethoxy-1-propoxy-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(5 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration.

C.3-(4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 15 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 210 mg. (M.p.149°-150° C.; M⁺ : 283; Compound 39).

EXAMPLE 37

A. 3-(4-(2-ethoxyethoxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride(410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (790 mg, 4 mmol) in drytetrahydrofuran. The mixture was stirred at room temperature for 2 h.Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated to give the title compound.

B. 3-(4-(2-ethoxyethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-(2-ethoxyethoxy)-1,2,5-thiadiazol-3-yl)pyridine (4 mmol) in acetone(3 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield1.45 g (92%).

C.3-(4-(2-ethoxyethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (350 mg, 9 mmol) was added to a solution of3-(4-(2-ethoxyethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(1.45 g, 3.7 mmol) in ethanol (99.9%, 15 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 640 mg. (M.p.153°-156° C.; M⁺ : 269; Compound 40).

EXAMPLE 38

A. 3-(4-(2-butoxyethoxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 2-butoxyethanol (1.06 g, 9 mmol) and sodium hydride(310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(2-butoxyethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-(2-butoxyethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone(4 ml) was stirred at room temperature for 18 h. The title compoundprecipitated from the solution and was collected by filtration to yield1.07 g (85%).

C.3-(4-(2-butoxyethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-(2-butoxyethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide(1.07 g, 2.5 mmol) in ethanol (99.9%, 20 ml) and the reaction mixturewas stirred at -10° C. for 1 h. After evaporation the residue wasdissolved in water and extracted with ethyl acetate. The dried organicphases were evaporated and the residue purified by column chromatography(SiO₂, eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 490 mg. (M.p.152°-153° C.; M⁺ : 297; Compound 41).

EXAMPLE 39

A. 3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 1 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B.3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol)in acetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.

C.3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6mmol) was added to a solution of3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 340 mg. (M.p.90°-91° C.; M⁺ : 341; Compound 42).

EXAMPLE 40

A. 3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine

To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodiumhydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B.3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 9 mmol) and3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol)in acetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtration.

C.3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 290 mg. (M.p.115°-116° C.; M⁺ : 313; Compound 43).

EXAMPLE 41

A. 3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl) pyridine

A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (10.80 g, 4mmol) and 4-methylpiperidine (1.96 g, 20 mmol) in DMF (10 ml) was heatedat 100° C. for 3 h. After evaporation water was added to the residue andextracted with ether. The combined and dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methylene chloride (1:2)). Yield: 0.8 g (77%).

B. 3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl)pyridine (0.8 g, 3.1mmol) in acetone (5 ml) was stirred at room temperature for 18 h. Thetitle compound precipitated from the solution and was collected byfiltration to yield 1.14 g (92%).

C.3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl)-1-methylpyridiniumiodide (1.14 g, 2.8 mmol) in ethanol (99.9%, 20 ml) and the reactionmixture was stirred at -10° C. for 1 h. After evaporation the residuewas dissolved in water and extracted with ethyl acetate. The driedorganic phases were evaporated and the residue purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone to yield 450mg. (M.p. 106°-107° C.; M⁺ : 278; Compound 44).

EXAMPLE 42

A. 3-(4-morpholino-1,2,5-thiadiazol-3-yl)pyridine

A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3mmol) and morpholine (1.3 g, 15 mmol) in DMF (5 ml) was heated at 100°C. for 3 h. After evaporation water was added to the residue andextracted with ether. The combined and dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methylene chloride (1:1)). Yield: 0.68 g (91%).

B. 3-(4-morpholino-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(4-morpholino-1,2,5-thiadiazol-3-yl)pyridine (680 mg, 2.7 mmol) inacetone (5 ml) was stirred at room temperature for 18 h. The titlecompound precipitated from the solution and was collected by filtrationto yield 1.0 g (94%).

C.3-(4-morpholino-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(4-morpholino-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (1.53g, 39 mmol) in ethanol (99.9%, 30 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 470 mg. (M.p.177°-178° C.; M⁺ : 266; Compound 45).

EXAMPLE 43

A. 3-(4-hexylamino-1,2,5-thiadiazol-3-yl)pyridine

A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3mmol) and hexylamine (1.52 g, 15 mmol) in DMSO (5 ml) was heated at 100°C. for 48 h. After evaporation, water was added to the residue andextracted with ether. The combined organic extract were dried andevaporated to give the title compound.

B. 3-(4-hexylamino-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.6 ml, 9.6 mmol) and3-(4-hexylamino-1,2,5-thiadiazol-3-yl)pyridine (3.2 mmol) in acetone (5ml) was stirred at room temperature for 18 h and evaporated.

C.3-(4-hexylamino-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(4-hexylamino-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (4.2mmol) in ethanol (99.9%, 25 ml) and the reaction mixture was stirred at-10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 490 mg. (M.p.102°-103° C.; M⁺ : 280; Compound 46).

EXAMPLE 44

A. 3-(4-propylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (220 m, 3 mmol) was added over 30 min. to asolution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol)in DMF (20 ml) at room temperature. Potassium carbonate (1.24 g, 9 mmol)and iodopropan (0.76 g, 4.5 mmol) were added. The reaction mixture wasstirred at room temperature for 30 min. Water was added and the mixtureextracted with ether. The combined ether phases were dried andevaporated to give the title compound in 89% (0.63 g) yield.

B. 3-(4-propylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (0.5 ml, 8 mmol) and3-(4-propylthio-1,2,5-thiadiazol-3-yl)pyridine (0.63 g, 2.6 mmol) inacetone (5 ml) was stirred at room temperature for 18 h and evaporated.

C.3-(4-propylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (200 mg, 5 mmol) was added to a solution of3-(4-propylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (2.6mmol) in ethanol (99.9%, 15 ml) and the reaction mixture was stirred at-10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 310 mg. (M.p.138°-139° C.; M⁺ : 255; Compound 47).

EXAMPLE 45

A. 3-(4-butylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (2 g, 14.5 mmol) and butyliodide (1 ml, 8.8 mmol)were added and the reaction mixture was stirred for additionally 10 min.Water (50 ml) was added and extracted with ether. The combined etherphases were dried and evaporated to give the title compound. Yield: 0.6g.

B. 3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(4-butylthio-1,2,5-thiadiazol-3-yl)pyridine (0.6 g, 2.3 mmol) and thereaction mixture was stirred at room temperature for 48 h andevaporated.

C.3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (2.3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 300 mg. (M.p. 148°-150° C.; M⁺ : 269;Compound 48).

EXAMPLE 46

A. 3-(4-methylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (2 g, 14.5 mmol) and methyliodide (1 ml, 15 mmol)were added and the reaction mixture was stirred for additionally 10 min.Water (50 ml) was added and extracted with ether. The combined etherphases were dried and evaporated to give the title compound. Yield: 0.5g.

B. 3-(4-methylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(4-methylthio-1,2,5-thiadiazol-3-yl)pyridine (0.5 g, 2.3 mmol) and thereaction mixture was stirred at room temperature for 48 h andevaporated.

C.3-(4-methylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (250 mg, 6.2 mmol) was added to a solution of3-(4-methylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (2.3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 300 mg. (M.p. 169°-170° C.; M⁺ : 227;Compound 49).

EXAMPLE 47

A. alpha-oximino-3-pyridylacetonitrile

3-pyridylacetonitrile (47.2 g, 400 mmol) was dissolved in a solution ofsodium hydroxide (16 g, 400 mmol) in methanol (100 ml). Methylnitrite,generated by dropping a solution of concentrated sulphuric acid (12.8ml) and water (26 ml) to a solution of sodium nitrite (33.2 g, 480 mmol)in water (20 ml) and methanol (20 ml), was bobled through the3-pyridylacetonitrile solution at 0° C. The reaction mixture was stirredat 0° C. for 1 h and the precipitate collected by filtration. Theprecipitate was washed with a little methanol to give the wanted productin 70% (41.1 g) yield. M⁺ : 147.

B. alpha-oximino-3-pyridylacetamidoxime

A mixture of alpha-oximino-3-pyridylacetonitrile (41.0 g, 279 mmol),hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8g, 620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. Aftercooling, the precipitate was collected by filtration and dried. Theprecipitate contained the wanted product and sodium acetate (85 g,168%); M⁺ : 180.

C. 3-(4-amino-1,2,5-oxadiaxol-3-yl)pyridine

Crude alpha-oximino-3-pyridylacetamidoxime (5 g) and phosphoruspentachloride (5) was refluxed in dry ether (250 ml) for 6 h. Water andpotassium carbonate to alkaline pH was added and the phases separated.The aqueous phase was extracted with ether and the combined ether phasesdried. Evaporation of the ether phases gave the title compound in 850 mgyield; M⁺ : 162.

D. 3-(4-amino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

To a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)pyridine (870 mg, 5.3mmol) in acetone (20 ml) was added methyl iodide (990 μl, 16 mmol) andthe reaction mixture was stirred overnight at room temperature. Thetitle compound precipitated and was collected by filtration (1.1 g,69%).

E. 3-(4-amino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (262 mg, 6.9 mmol) was added to a solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (1.05 g, 3.45mmol) in methanol (80 ml) at 0° C. After 15 min. water (40 ml) was addedand the mixture extracted with ether. The ether phase was dried,evaporated and purified by column chromatography (eluent: ethylacetate:methanol (2:1)). Crystallization from acetone with oxalic acidgave the title compound in 310 mg (50%) yield. (M.p. 181°-183° C.; M⁺ :180; Compound 50).

EXAMPLE 48

A. 3-(4-acetylamino-1,2,5-oxadiazol-3-yl)pyridine

Crude hydroxyimino-3-pyridylmethylamidoxime (4.5 g) and polyphosphoricacid (49 g) was stirred at 100° C. for 18 h. After cooling to roomtemperature aqueous ammonia (25%) was added slowly to pH >9 and theprecipitate collected by filtration. The precipitate was dissolved inwater and extracted with methylene chloride. The organic phases weredried and evaporated to give the title compound in 430 mg yield.

B. 3-(4-acetylamino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (450 μl, 7.2 mmol) was added to a solution of3-(4-acetylamino-1,2,5-oxadiazol-3-yl)pyridine (490 mg, 2.4 mmol) inacetone. The reaction mixture was stirred at room temperature for 18 hand the precipitate collected by filtration. Yield: 640 mg (77%).

C.3-(4-acetylamino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (140 mg, 3.7 mmol) was added to a solution of3-(4-acetylamino-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (640mg, 1.85 mmol) in methanol (15 ml) at 0° C. After 15 min. water (10 ml)was added and the reaction mixture extracted with ether. The combinedether phases were dried and evaporated. Crystallization from acetonewith oxalic acid gave the title compound in 140 mg yield. (M.p.180°-184° C.; M⁺ : 222; Compound 51).

EXAMPLE 49

A. 3-(1,2,5-oxadiazol-3-yl)pyridine and3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine

To a solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)pyridine (1.0 g, 6.2mmol) in glacial acetic acid (16 ml) and concentrated hydrochloric acid(5.2 ml) was added CuCl₂ (938 mg, 7 mmol) and cupper coils (100 mg) at0° C. After 10 min. a solution of sodium nitrite (483 mg, 7 mmol) inwater (3 ml) was added dropwise at 5° C. The reaction mixture wasstirred additionally 30 min. at 0° C. Aqueous sodium hydroxide (2N) wasadded to alkaline pH and the mixture extracted with ether. The etherphases were dried and evaporated to give a mixture of the titlecompounds. Separation by column chromatography (SiO₂, eluent: ethylacetate) gave the chloro compound, upper spot, in 230 mg yield, and theunsubstituted product, lower spot, in 60 mg yield.

B. 3-(4-chloro-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (230 mg, 1.2 mmol) in acetone.The reaction mixture was stirred at room temperature for 18 h andevaporated to give the title compound.

C. 3-(4-chloro-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (119 mg, 3.2 mmol) was added to a solution of3-(4-chloro-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (1.2 mmol)in methanol (5 ml) at 0° C. After 15 min. water was added and themixture extracted with ether. The ether phases were dried andevaporated. Crystallization from acetone with oxalic acid andrecrystallization from acetone gave the title compound in 60 mg yield.(M.p. 126°-129° C.; M⁺ : 198 and 200; Compound 52).

EXAMPLE 50

A. 3-(1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(1,2,5-oxadiazol-3-yl)pyridine (430 mg, 2.9 mmol) in acetone (20 ml).The reaction mixture was stirred at room temperature for 18 h. Theproduct precipitated from the solution and the title compound wascollected by filtration in 82% (700 mg) yield.

B. 3-(1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

Sodium borohydride (168 mg, 4.4 mmol) was added to a solution of3-(1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (640 mg, 2.2 mmol) inmethanol (15 ml) and water (2 ml) at 0° C. After 15 min. water was addedand the mixture extracted with ether. The combined ether phases weredried and evaporated. The residue was crystallized as the oxalate saltfrom acetone giving the title compound in 100 mg yield. (M.p. 238°-240°C. dec.; M⁺ : 165; Compound 53).

EXAMPLE 51

A. 3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)pyridine

To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 ml) wasadded 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (180 mg, 1 mmol). Themixture was stirred at 25° C. for 18 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the title compound.

B. 3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1 ml, 15 mmol) and3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)pyridine (1 mmol) in acetone (5 ml)was stirred at room temperature for 18 h and evaporated to give thetitle compound.

C.3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (76 mg, 2 mmol) was added to a solution of3-(4-hexyloxy-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (1 mmol)in methanol (5 ml) and the reaction mixture was stirred at 0° C. for 15min. After evaporation the residue was dissolved in water and extractedwith ether. The dried organic phases were evaporated and the residuepurified by column chromatography (SiO₂, eluent: ethyl acetate/methanol(4:1)). The title compound was crystallized as the oxalate salt fromacetone to yield 60 mg. (M.p. 143°-147° C.; M⁺ : 265; Compound 54).

EXAMPLE 52

A. 3-(4-butyloxy-1,2,5-oxadiazol-3-yl)pyridine

To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (350 mg, 1.9 mmol). Themixture was stirred at 25° C. for 2 h and evaporated. The residue wasdissolved in water and extracted with ether. The combined organic phaseswere dried and evaporated to give the title compound.

B. 3-(4-butyloxy-1,2,5-oxadiazol-3-yl)-1-methylpyridine iodide

A mixture of methyl iodide (1 ml, 15 mmol) and 3-(4-butyloxy-1,2,5-oxadiazol-3-yl)pyridine (1.9 mmol) in acetone (10 ml) was stirred atroom temperature for 18 h and evaporated.

C.3-(4-butyloxy-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (148 mg, 3.8 mmol) was added to a solution of3-(4-butyloxy-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (1.9 mmol)in methanol (20 ml) and the reaction mixture was stirred at 0° C. for 15min. After evaporation the residue was dissolved in water and extractedwith ether. The dried organic phases were evaporated and the residuepurified by column chromatography (SiO₂, eluent: ethyl acetate/methanol(4:1)). The title compound was crystallized as the oxalate salt fromacetone to yield 120 mg. (M p. 132°-135° C.; M⁺ : 237; Compound 55).

EXAMPLE 53

A. 3-(4-(3-hexynyloxy)-1,2,5-oxadiazol-3-yl)pyridine

To a solution of 3-hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240mg, 10 mmol) in dry tetrahydrofuran was added a solution of3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (450 mg, 2.5 mmol) in drytetrahydrofuran. The reaction mixture was stirred at room temperaturefor 2 h. Water was added and the mixture was extracted with ether. Theether phase was dried and evaporated to give the title compound.

B. 3-(4-(3-hexynyloxy)-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide

A mixture of methyl iodide (1.5 ml, 22 mmol) and3-(4-(3-hexynyloxy)-1,2,5-oxadiazol-3-yl)pyridine (2.5 mmol) in acetone(20 ml) was stirred at room temperature for 18 h and evaporated to givethe title compound.

C.3-(4-(3-hexynyloxy)-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (190 mg, 5 mmol) was added to a solution of3-(4-(3-hexynyloxy)-1,2,5-oxadiazol-3-yl)-1-methylpyridinium iodide (2.5mmol) in methanol (20 ml) and the reaction mixture was stirred at 0° C.for 15 min. After evaporation the residue was dissolved in water andextracted with ether. The dried organic phases were evaporated and theresidue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 50 mg. (M.p. 159°-161° C.; M⁺ : 261;Compound 56).

EXAMPLE 54

3-(4-pentyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of pentylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated.

The residue was crystallized as the oxalate salt from acetone in 300 mg(58%) yield. Recrystallization from ethanol gave the title compound in125 mg (24%) yield. (M.p. 156°-157° C.; M⁺ : 251; Compound 57).

EXAMPLE 55

3-(4-heptyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of heptylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was crystallized as the oxalatesalt from acetone in 400 mg (73%) yield. (M.p. 151°-152° C.; M⁺ : 274;Compound 58).

EXAMPLE 56

3-(4-(5-hexenyl)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridinium oxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of 5-hexenylmagnesium bromide (1.5 mmol) in tetrahydrofuran at0° C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone in 340 mg(64%) yield. (M.p. 113°-115° C.; M⁺ : 263; Compound 59).

EXAMPLE 57

3-(4-octyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of octylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0°C. The reaction mixture was stirred for 10 min. and water (20 ml) wasadded. The product was extracted with ether (3×100 ml) and the driedether phases evaporated. The residue was purified by columnchromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). The titlecompound was crystallized as the oxalate salt from acetone in 430 mg(75%) yield. (M.p. 157°-158° C.; M⁺ : 293; Compound 60).

EXAMPLE 58

3-(4-isobutyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(300 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of isobutoxybutylmagnesium bromide (1.5 mmol) intetrahydrofuran at 0° C. The reaction mixture was stirred for 10 min.and water (20 ml) was added. The product was extracted with ether (3×100ml) and the dried ether phases evaporated. The residue was purified bycolumn chromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). Thetitle compound was crystallized as the oxalate salt from acetone in 350mg (76%) yield. (M.p 148°-149° C.; M⁺ : 237; Compound 61).

EXAMPLE 59

3-(4-cyclopropylmethyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(300 mg, 1.4 mmol) in tetrahydrofuran (20 ml) was added slowly asolution of cyclopropylmethylmagnesium bromide (1.5 mmol) intetrahydrofuran at 0° C. The reaction mixture was stirred for 10 min.and water (20 ml) was added. The product was extracted with ether (3×100ml) and the dried ether phases evaporated. The residue was purified bycolumn chromatography (SiO₂, eluent: ethyl acetate/methanol (4:1)). Thetitle compound was crystallized as the oxalate salt from acetone in 380mg (83%) yield. (M.p. 147°-148° C.; M⁺ : 235; Compound 62).

EXAMPLE 60

3-(4-propyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridiniumoxalate

To a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine(450mg, 1.5 mmol) in tetrahydrofuran (20 ml) was added slowly a solution ofpropylmagnesium bromide (1.5 mmol) in tetrahydrofuran at 0° C. Thereaction mixture was stirred for 10 min. and water (20 ml) was added.The product was extracted with ether (3×100 ml) and the dried etherphases evaporated. The residue was crystallized as the oxalate salt fromacetone in 350 mg (75%) yield. (M.p. 141°-142° C.; M⁺ : 223; Compound63).

EXAMPLE 61

A. 3-(4-octylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and 1-bromooctane (0.80 ml, 4.5mmol) were added and the reaction mixture was stirred for additionally10 min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(4-octylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridine iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(4-octylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(4-octylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(4-octylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C.for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 400 mg. (M.p. 121°-122° C.; M⁺ : 325;Compound 64).

EXAMPLE 62

A. 3-(4-ethylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and ethyl iodide (0.36 ml, 4.5mmol) were added and the reaction mixture was stirred for additionally10 min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(4-ethylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(4-ethylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(4-ethylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (270 mg, 7 mmol) was added to a solution of3-(4-ethylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C.for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 490 mg (M.p 145°-146° C.; M⁺ : 241;Compound 65).

EXAMPLE 63

3-(4-pentylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and pentyl bromide (700 mg, 4.5mmol) were added and the reaction mixture was stirred for additionally10 min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(4-pentylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinum iodide

Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of3-(4-pentylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(4-pentylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (300 mg, 8 mmol) was added to a solution of3-(4-pentylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (3mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at0° C. for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 430 mg. (M.p. 136°-138° C.; M⁺ : 283;Compound 66).

EXAMPLE 64

A. 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)pyridine

Sodium hydrogen sulfide (0.25 g, 3.3 mmol) was added to a solution of3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) in DMF (20ml) at room temperature and the reaction mixture was stirred for 30 min.Potassium carbonate (1.24 g, 9 mmol) and hexyl bromide (0.63 ml, 4.5mmol) were added and the reaction mixture was stirred for additionally10 min. Water (50 ml) was added and extracted with ether. The combinedether phases were dried and evaporated to give the title compound.

B. 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(4-hexylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reactionmixture was stirred at room temperature for 48 h and evaporated.

C.3-(4-hexylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (230 mg, 6 mmol) was added to a solution of3-(4-hexylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodine (3 mmol)in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at 0° C.for 1 h. After evaporation the residue was dissolved in water andextracted with ethyl acetate. The dried organic phases were evaporatedand the residue purified by column chromatography (SiO₂, eluent: ethylacetate/methanol (4:1)). The title compound was crystallized as theoxalate salt from acetone to yield 350 mg. (M.p. 126°-127° C.; M⁺ : 297;Compound 67).

It is to be understood that the invention is not to be limited to theexact details of operation, or to the exact compounds, compositions,methods, procedures, or embodiments shown and described, as obviousmodifications and equivalents will be apparent to one skilled in theart, and the invention is therefore to be limited only by the full scopeof the appended claims.

We claim:
 1. A compound of formula I ##STR12## wherein Z is oxygen orsulphur;R is H, C₁₋₃ -alkyl, C₃₋₄ -cycloalkyl, C₂₋₄ -alkenyl or C₂₋₄alkynyl; and R¹ is H, --C₁₋₁₅ -alkyl, --C₂₋₁₅ -alkenyl, --C₃₋₇ -alkynyl,--C₃₋₇ -cycloalkyl, morpholino, --C₁₋₆ -alkyl substituted piperidino,--C₁₋₆ acylamino, --C₁₋₁₅ -alkylamino, --C₁₋₅ -dialkylamino, --C₁₋₁₅-alkoxyamino, --S--R² or --O--R² wherein R² is straight or branched--C₁₋₁₅ -alkyl, straight or branched --C₂₋₁₅ -alkenyl, or straight orbranched --C₂₋₁₅ alkynyl; or a pharmaceutically acceptable salt thereof.2. A compound according to claim 1, wherein Z is sulphur.
 3. A compoundaccording to claim 1 whichis1,2,5,6-tetrahydro-3-(4-methoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine;3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-tetrahydro-1-methyl-3-(4-propoxy-1,2,5-thiadiazol-3-yl)pyridine;1,2,5,6-tetrahydro-3-(4-isopropoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine;1,2,5,6-tetrahydro-1-methyl-3-(4-pentyloxy-1,2,5-thiadiazol-3-yl)pyridine;1,2,5,6-tetrahydro-3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine;1,2,5,6-tetrahydro-3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)-1-methylpyridine;3-(4-butoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridine;3-(4-ethoxy-1,2,5-thiadiazol-3-yl)-1-ethyl-1,2,5,6-tetrahydropyridine;3-(4-heptyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-octyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-tetrahydro-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 which is3-(4-cyclopropylmethoxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-cyclopropylmethyl1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine; or apharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1 whichis3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydropyridine;3-(4-chloro-1,2,5-thiadiazol-3-yl)-1-ethyl-1,2,5,6-tetrahydropyridine;or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1 whichis3-(4-(3-butenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;1,2,5,6-tetrahydro-1-methyl-3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)pyridine;3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(4-pentenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(2-propenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(3methyl-2-butenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(3-butenyl-2-oxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;cis-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;trans-3-(4-(2-hexenyloxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 1 whichis3-(4-(2-(2-methoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(3-ethoxy-1-propoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(2-(2-butoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1 which is3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineor a pharmaceutically acceptable salt thereof.
 9. A compound accordingto claim 1 which is3-(4-morpholino-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineor a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1 which is3-(4-hexylamino-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineor a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 whichis3-(4-propylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-methylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4- octylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-ethylthio-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 whichis3-(4-amino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-acetylamino-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-chloro-1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(1,2,5-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine; or apharmaceutically acceptable salt thereof.
 13. A compound according toclaim 1 whichis3-(1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-pentyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-heptyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-octyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-isobutyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(4-propyl-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1 whichis3-(5-hexenyl)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridineor a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1 together with a pharmaceutically acceptable carrier or diluent.16. The pharmaceutical composition according to claim 15 in the form ofan oral or parenteral dosage unit.
 17. The pharmaceutical compositionaccording to claim 16, wherein the dosage unit comprises from about 1 toabout 100 mg of the compound.
 18. A method of stimulating the cognitivefunctions of the forebrain and hippocampus in a subject in need thereof,comprising administering to the subject an effective amount of acompound according to claim
 1. 19. A method of stimulating the cognitivefunctions of the forebrain and hippocampus in a subject in need thereof,comprising administering to the subject an a pharmaceutical compositionaccording to claim
 15. 20. A method of treating Alzheimer's disease in asubject in need thereof, comprising administering to the subject aneffective amount of a compound according to claim
 1. 21. A method oftreating Alzheimer's disease in a subject in need thereof, comprisingadministering to file subject a pharmaceutical composition according toclaim
 15. 22. A method of providing an analgesic effect in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound according to claim
 1. 23. A method of providing ananalgesic effect in a subject in need thereof, comprising administeringto the subject a pharmaceutical composition according to claim 15.